Page EL, Chan DA, Giaccia AJ, Levine M, Richard DE

Centre de recherche de L'Hotel-Dieu de Quebec, Department of Medicine, Universite Laval, Quebec, QC, G1R 2J6, Canada.

Hypoxia-inducible factor-1 (HIF-1) is a decisive element for the transcriptional regulation of many genes induced under low oxygen conditions. Under normal oxygen conditions, HIF-1alpha, the active subunit of HIF-1, is hydroxylated on proline residues by specific HIF prolyl-hydroxylases, leading to ubiquitination and degradation by the proteasome. In hypoxia, hydroxylation and ubiquitination are blocked and HIF-1alpha accumulates in cells. Recent studies have shown that in normal oxygen conditions G-protein-coupled receptor agonists, including angiotensin (Ang) II and thrombin, potently induce and activate HIF-1 in vascular smooth muscle cells. The current study identifies HIF-1alpha protein stabilization as a key mechanism for HIF-1 induction by Ang II. We show that hydroxylation on proline 402 is altered by Ang II, decreasing pVHL binding to HIF-1alpha and allowing HIF-1alpha protein to escape subsequent ubiquitination and degradation mechanisms. We show that HIF-1alpha stability is mediated through the Ang II-mediated generation of hydrogen peroxide and a subsequent decrease in ascorbate levels, leading to decreased HIF prolyl-hydroxylase activity and HIF-1alpha stabilization. These findings identify novel and intricate signaling mechanisms involved in HIF-1 complex activation and will lead to the elucidation of the importance of HIF-1 in different Ang II-related cell responses.

Mesh Terms:
Angiotensin II, Animals, Ascorbic Acid, Cell Hypoxia, Coenzymes, Half-Life, Humans, Hydrogen Peroxide, Hydroxylation, Hypoxia-Inducible Factor 1, alpha Subunit, Intracellular Space, Male, Oxidation-Reduction, Procollagen-Proline Dioxygenase, Protein Binding, Protein Processing, Post-Translational, Protein Structure, Tertiary, Rats, Rats, Wistar, Thermodynamics, Ubiquitination, Von Hippel-Lindau Tumor Suppressor Protein

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